COlchicine for the Prevention of Post Electrical Cardioversion Recurrence of AF (COPPER-AF)

Colchicine for the Prevention of Atrial Fibrillation Recurrence After Electrical Cardioversion of Persistent Atrial Fibrillation.

There is substantial evidence linking inflammation to the initiation and perpetuation of AF. Although the precise mechanism by which inflammation contributes to the development of AF remains unclear, it has been proposed that inflammation may lead to "atrial myocarditis" with subsequent electrical and structural changes involving both atrial myocytes and extracellular matrix, leading finally to initiation and maintenance of AF. The high incidence of AF in post-operative cardiac surgeries, a state of intense inflammatory process, points out this association. Similarly, in non operative AF, inflammation appears to play a prominent role in both etiology and maintenance of AF. Indeed an increase of inflammatory markers to both paroxysmal and persistent AF was shown by numerous studies.

In particular, CRP levels in patients with persistent AF are higher than in those with paroxysmal AF, and levels in both groups are higher than those in the control group. Moreover, hs-CRP and IL-6 levels have been reported as markers that may identify those patients with a higher risk of AF recurrence after successful electrical cardioversion (EC), providing prognostic information regarding the immediate and long-term success of EC. CRP is an acute-phase protein and a reliable marker of systemic inflammation. CRP has been shown to specifically bind to phosphatidylcholine on the membranes of myocardial cells which inhibits the exchange of sodium and calcium ions in sarcolemma vesicles, promoting therefore AF development. CRP may also play a part in the structural remodeling; it may induce apoptotic loss of atrial myocytes because of calcium accumulation within atrial myocytes during AF participating also in the clearance of apoptotic atrial myocytes as an opsonin. Myocyte loss is typically accompanied by replacement fibrosis which provides substrate for AF development. IL-6 is one of the most important stimuli of CRP release. As the strongest stimuli of macrophage, TNF-α is in the upstream of this cascade by activating macrophage to release a number of cytokines including IL-6. Whether inflammatory effects are a consequence of AF or the presence of a pre-existing systemic inflammatory status promotes AF development remains unclear. However, accumulative proofs have implied that both mechanisms may interrelate, suggesting that inflammatory markers are not only a consequence but also a cause. Consequently, pharmacological interventions with pleiotropic/anti-inflammatory effects might be efficacious in the prevention of AF by modulating inflammatory pathways.(17) Keeping with this, several agents with anti inflammatotory properties as statins, fatty acids, oral glucocorticoids, nonsteroidal anti-inflammatory drugs, angiotensin converting enzyme inhibitors have been administered with controversial results. Colchicine is a lipid-soluble drug classified as an anti-inflammatory agent. It exerts its anti-inflammatory action without involving the arachidonic acid pathway affected by NSAIDs and glucocorticosteroids. The anti-inflammatory effects of colchicine are attributed to its ability to disrupt the assembly of microtubules in immune-mediated cells. By inhibiting tubulin polymerization, colchicine prevents the activation, degranulation, and migration of neutrophils, which are known initiating factors in inflammatory process. It has also been found to increase leukocyte cyclic adenosine monophosphate levels, inhibit interleukin-1 (IL-1) production by activated neutrophils and down-regulate tumor necrosis factor alpha (TNFa) receptors in macrophages and endothelial cells. Clinical evidence support that colchicine administration reduced significantly the incidence of AF post-cardiac surgery (POAF) or post-AF ablation and this effect was attributed to the drug anti-inflammatory action. Of note, this effect was accompanied by a significant decrease in inflammatory mediators, IL-6 and CRP as it was shown in post-AF ablation patients.(33) Additional mechanisms may play also a role in the reduction of POAF or post-ablation AF as in vitro or animal studies showed colchicine administration to exert electrophysiological effects related to cytoskeletal disruption. All patients will undergo echocardiography and blood examination (including thyroid function, renal and liver function tests, lipid assessment, international normalized ratio and foul blood cell count) before EC. Blood samples for CRP, IL-6 and TNFa measurement will be obtained immediately before ECV (day 0), one day after successful ECV (day 1) and after 3 days of colchicine treatment (day 4). Anticoagulation therapy will be instituted according to the current guidelines. If there is indication for transesophageal echocardiography this will be performed prior to EC. The protocol of electrical cardioversion will be as follows: a shock will be delivered with external paddles positioned in the anterior-apex position connected to an external electrical cardioverter for biphasic external cardioversion. The first shock energy will be delivered at 200 J following a step-up protocol (to 300 J). In case of unsuccessful ECV, a second attempt in anteroposterior position could be made. ECV will be considered successful if sinus rhythm remains 24 hrs after the procedure. Successfully cardioverted patients will be entered the maintenance phase of the study and treatment will be continued for up to 6 months

Inclusion Criteria: patients experiencing their first episode of AF of less than 3 months duration will be given no other antiarrhythmic drugs but b-blocker In case of recurrent episodes of AF or if AF duration is >3 months patients on antiarrhythmic drugs of class IC or III as first choice. men and women 18 to 80 years of age with persistent AF (sustained for > 7 days) for which electrical cardioversion was indicated. Exclusion Criteria: active inflammatory or infectious disease malignancy known autoimmune diseases corticosteroid or other immunosuppressive or immunomodulatory therapy drugs that inhibit CYP3A4 (clarithromycin, azithromycin, ketoconazole, ritonavir, verapamil, and diltiazem) moderate or severe hepatic impairment (Child-Pugh class B or C) moderate or severe renal failure (≤ 40 ml/min per 1.73 m2) acute coronary syndrome within a month before study enrollment known blood dyscrasias or gastrointestinal disease pregnant and lactating women women of childbearing potential not protected by a contraception method - patients with atrial flutter will be also excluded unless there is history of coexisting AF.

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